Stimulation of dichlorofluorescin oxidation by capsaicin and analogues in RAW 264 monocyte/macrophages: lack of involvement of the vanilloid receptor

In studies into the oxidative burst in RAW 264 monocyte/macrophages, it was observed that capsaicin, a vanilloid receptor agonist, stimulated dichlorofluorescin (DCFH) oxidation in a concentration-dependent manner, which could be blocked by capsazepine, a vanilloid receptor antagonist. However, by use of a number of vanilloid agonists (including N-octyl-3-chloro-4-hydroxyphenylacetamide, 4m), we demonstrated that there was no relationship between vanilloid agonist potency and the capacity to stimulate DCFH oxidation. The oxidative burst stimulators Tween 20 and phorbol myristyl acetate (PMA) also stimulated reactive oxygen species generation, which again was inhibited by capsazepine. Use of the selective inhibitor diphenyliodonium iodide ruled out a role for plasma membrane NAD(P)H oxidase as the site of capsaicin- and 4m-stimulated DCFH oxidation. However, this DCFH oxidation was modulated by a number of inhibitors of mitochondrial respiration. Rotenone enhanced DCFH oxidation induced by capsaicin and 4m, whilst malonic acid and potassium cyanide inhibited this response. 2,4-Dinitrophenol, an inhibitor of oxidative phosphorylation, was without effect. The antioxidant trolox c inhibited DCFH oxidation stimulated by capsaicin, 4m, and PMA, whereas N-acetylcysteine, a precursor of glutathione, was without effect. Capsazepine inhibited DCFH oxidation in unstimulated cells and in cells treated with menadione, a redox-cycling quinone. Capsazepine was also a potent antioxidant when measured in a Fe3+ reduction assay. We concluded that DCFH oxidation stimulated by vanilloid analogues was not mediated via a vanilloid receptor, but rather by impairment of mitochondrial electron transport.     

Selectivity of 7-alkoxycoumarins as probe substrates for rat hepatic cytochrome P450 forms is influenced by the substitution pattern on the coumarin nucleus

1. The O-dealkylation of 7-alkoxycoumarins is widely used as an assay to characterize cytochrome P450 (CYP) activity. These substrates can also undergo oxidative attack at additional sites on the coumarin nucleus, which may influence their apparent selectivity for particular CYP forms.

2. Accordingly, the effect of blockade of these additional sites was investigated on the selectivity towards rat hepatic CYP forms, with emphasis on the CYP1A and 2B forms.

3. Blockade of the 3-/4- and 6-positions resulted in substrates for which the CYP1A1/2 selectivity of the unsubstituted 7-alkoxycoumarins was altered to a CYP2B selectivity; this was achieved with little overall change in the molecular dimensions of the substrate. Limited analysis of other inducible CYP forms indicated at most only small effects of structure modification on activity.

4. The findings suggest that the sensitivity of probe substrates for CYP forms may be limited by the occurrence of competing side reactions of the substrate, and that better probes may be derived by blocking the sites of these side reactions.

     

Modified Cognitive Behavior Therapy for Severe,Treatment‐Resistant Obsessive‐Compulsive Disorder in an Adolescent With Autism Spectrum Disorder

There is a high rate of comorbidity between obsessive‐compulsive disorder (OCD) and autism spectrum disorders (ASD). Standard cognitive‐behavior therapy (CBT) protocols have been shown to be less effective in treating OCD in young people with ASD than in typically developing youth. This case study describes the treatment of an adolescent boy with severe, treatment‐resistant OCD and ASD using a modified CBT approach. Modifications to a standard evidence‐based CBT for OCD protocol included extended psychoeducation about anxiety; regular home‐based sessions; and increased involvement of systems, including family and school. Multi‐informant outcome data indicated significant improvements in OCD symptoms over the course of treatment with gains being maintained over a 12‐month follow‐up period. These findings demonstrate the potential efficacy of modified CBT for pediatric OCD in the context of ASD.     

The Ritvo Autism Asperger Diagnostic Scale-Revised (RAADS-R): A Scale to Assist the Diagnosis of Autism Spectrum Disorder in Adults: An International Validation Study

The Ritvo Autism Asperger Diagnostic Scale-Revised (RAADS-R) is a valid and reliable instrument to assist the diagnosis of adults with Autism Spectrum Disorders (ASD). The 80-question scale was administered to 779 subjects (201 ASD and 578 comparisons). All ASD subjects met inclusion criteria: DSM-IV-TR, ADI/ADOS diagnoses and standardized IQ testing. Mean scores for each of the questions and total mean ASD vs. the comparison groups' scores were significantly different (p?相似文献   

An Evaluation of a New Autism-Adapted Cognitive Behaviour Therapy Manual for Adolescents with Obsessive–Compulsive Disorder

Obsessive–compulsive disorder (OCD) and autism spectrum disorder (ASD) frequently co-occur. Standard cognitive behaviour therapy (CBT) for OCD outcomes are poorer in young people with ASD, compared to those without. The aim of this naturalistic study was to evaluate the effectiveness of a novel adolescent autism-adapted CBT manual for OCD in a specialist clinical setting. Additionally, we examined whether treatment gains were maintained at 3-month follow-up. Thirty-four adolescents underwent CBT; at the end of treatment, 51.51% were treatment responders and 21.21% were in remission. At 3-month follow-up, 52.94% were responders and 35.29% remitters. Significant improvements were also observed on a range of secondary measures, including family accommodation and global functioning. This study indicates this adapted package of CBT is associated with significant improvements in OCD outcomes, with superior outcomes to those reported in previous studies. Further investigation of the generalizability of these results, as well as dissemination to different settings, is warranted.

     

Star-Shape Kinesio Taping Is Not Better Than a Minimal Intervention or Sham Kinesio Taping for Pain Intensity and Postural Control in Chronic Low Back Pain: A Randomized Controlled Trial

ObjectiveThis study investigated the effects of star-shape Kinesio taping (KT) compared with both sham KT and minimal intervention (MI) on pain intensity and postural control.DesignRandomized controlled trial.SettingOutpatient physical therapy.ParticipantsA total of 120 people with chronic low back pain (CLBP) aged 18-60 years (N=120).InterventionsStar-shape KT, sham KT (no tension), and MI (educational booklet for self-management counseling).Main Outcome MeasuresThe primary outcome measures were pain intensity and center of pressure (COP) mean sway speed, and disability score (Oswestry Disability Index) was a secondary outcome. The outcomes were obtained immediately after initial KT application, on the seventh day of intervention and at the 1-month follow-up. Linear mixed-model analyses using Bonferroni post hoc analyses were applied to investigate between-group differences. The model included treatment, time, and treatment×time interaction as fixed effects.ResultsPain intensity was significantly lower for the star-shape KT group than for the MI group (mean difference [MD], ?1.35; 95% confidence interval [CI], ?2.63 to ?0.07) immediately after the intervention and on the seventh day of intervention (MD, ?1.32; 95% CI, ?2.56 to ?0.07). No difference in pain intensity between star-shape KT vs sham-KT groups was observed. In addition, no significant between-group differences were observed for the COP mean sway speed and disability score at any of the follow-up times.ConclusionsOur results showed no meaningful effect of star-shape KT intervention on pain intensity and postural control in people with CLBP compared with MI or sham KT. The observed reduction of 1.3 units between star-shape KT and MI groups was statistically different, but it could not be considered clinically relevant. The results of this trial suggest that benefits from KT are more likely attributable to contextual factors rather than specific taping parameters.     

VascuSynth: Simulating vascular trees for generating volumetric image data with ground-truth segmentation and tree analysis

Automated segmentation and analysis of tree-like structures from 3D medical images are important for many medical applications, such as those dealing with blood vasculature or lung airways. However, there is an absence of large databases of expert segmentations and analyses of such 3D medical images, which impedes the validation and training of proposed image analysis algorithms. In this work, we simulate volumetric images of vascular trees and generate the corresponding ground-truth segmentations, bifurcation locations, branch properties, and tree hierarchy. The tree generation is performed by iteratively growing a vascular structure based on a user-defined (possibly spatially varying) oxygen demand map. We describe the details of the algorithm and provide a variety of example results.